J. Am. Chem. SOC.1992, 114, 8707-8708
proton N M R and TLC. Lactone 17 was a mixture of stereoisomers at the newly-generated stereogenic center a to the carbonyl group. Keto ester 18 cyclized to hydroxy lactone 19 in 49% yield. The cyclization of keto ester 18 to an eight-membered-ring lactone rather than a six-membered-ring lactone was unexpected. A 1,g-hydrogen atom abstraction reaction via the syn rotamer of the ester followed by rapid closure of the proximate biradial nicely rationalizes this result. Similarly, keto ester 20 cyclized exclusively to the eight-membered-ring lactone 21 in 31% yield. 0
19: R-H, R'=Me
18: R = H , R = M e 2 0 R=Me, R ' = H
21: R=Me, R = H
The results presented herein demonstrate the potential of using either photochemically generated 1,4-biradicals or 1,g-hydrogen abstractions for ring-forming reactions. Extension to other photochemical reactions that proceed by way of 1,4-biradicals is in progress. Although the synthetic utility of this strategy remains to be determined, seven- and eight-membered oxacyclic rings are common subunits in certain families of marine natural products.13 (13) Faulkner, D. Nut. Prod. Rep. 1986, 3, 1
Regioselective and Endo-Stereoselective [3 + 21 Cycloaddition of Dipolar Trimethylenemethane to Electron-Deficient Olefin Satoshi Ejiri, Shigeru Yamago, and Eiichi Nakamura* Department of Chemistry, Tokyo Institute of Technology, Meguro, Tokyo 152, Japan Received July 13, 1992
Stereoselective synthesis of fivemembered carbocycles continues to attract the interest of organic chemists.lV2 We report that the
+
(1) (3 21 construction of five-membered carbocycles: (a) Noyori, R.; Hayakawa, Y. Org. React. 1983,29, 163. (b) Becker, D. A.; Danheiser, R. L. J . Am. Chem. Soc. 1989, 1 1 1 , 389 and references therein. (c) Feldman, K. S.; Romanelli, A. L.; Ruckle, R. E., Jr.; Miller, R. F. J . Am. Chem. SOC. 1988, 110, 3300. (d) Cekovic, Z . ; Saicic, R. Tetrahedron Lett. 1986, 27, 357. . Am. 1987.109.6558. (el Hemdon. Curran. --..-.D.P.:, Chen. . ~ M.-H. ~ ~~. . J~ ~ Chem. , ~ Soc. ~ .~ J. W.; Wu, C.; Harp, J. J.; Kreutzer, K. A. Synlett. 1991, 1. (fi Beak, P.f Wilson, K. D. J. Org. Chem. 1987, 52, 3826. (g) Gray, B. D.; McMillan, J. A,; Moore, M. Tetrahedron Lett. 1987,28,689. (h) Boger, D. L.; Brotherton, C. E. J . Am. Chem. SOC.1986, 108, 6695. Boger, D. L.; Brotherton-Pleiss, C. E. Aduances in Cycloaddition; Curran, D. P., Ed.; JAI Press: Greenwich, CT, 1990; Vol. 2, pp 147-219. (i) Marino, J. P.; Laborde, E. J . Am. Chem. Soc. 1985, 107, 734. 6 ) Beal, R. B.; Dombroski, M. A,; Snider, B. B. J . Org. Chem. 1986,51,4391. (k) Shimizu, I.; Ohashi, Y.; Tsuji, J. Tetrahedron Lett. 1985, 26, 3825. (I) Rosenblum, M.; Watkins, J. C. J . Am. Chem. Sor. 1990, 112,6322 and references therein. (m) Eidenschink, R.; Kauffmann, T. Angew. Chem., Int. Ed. Engl. 1972, 11, 292. (n) Boche, G.;Martens, P. Angew. Chem., Int. Ed. Engl. 1972, 11, 724. ( 0 ) Tokuyama, H.; Isaka, M.; Nakamura, E. J . Am. Chem. SOC.,in press. (2) (a) Reviews on TMM: Little, R. D.; Masjedizadeh, M. R.; Moeller, K. D.; Dannecker-Doerig, I. Synlett 1992, 107. Berson, J. A. Acc. Chem. Res. 1978, 11, 486. Dowd, P. Acr. Chem. Res. 1972, 5, 242. (b) Metal-mediated TMM chemistry: Noyori, R.; Yamakawa, M.; Takaya, H. Tetrahedron Left. 1978, 4823 and references cited therein. Binger, P.; Buchi, H. M. Top. Curr. Chem. 1987,135,77. Trost, B. M. Angew. Chem., Int. Ed. Engl. 1986, 25, 1. Aumann, R.; Uphoff, J. Angew. Chem., Int. Ed. Engl. 1987, 26, 357. Lewis, R. T.; Motherwell, M. B.; Shipman. M. J. J . Chem. SOC.,Chem. Commun. 1988, 948. Yamago, S . ; Nakamura, E. J. Chem. SOC.,Chem. Commun. 1988, 11 12. Yamago, S.; Nakamura, E. Tetrahedron 1989, 45, 3081. (c) Reviews on [3 + 21 cycloadditions: Padwa, A. 1.3-Dipolar Cycloaddition Chemistry; Wiley & Sons: New York, 1984; Vols. 1 and 2. Little, R. D. Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5 , pp 239-270.
~._ ~
~~
~
~
~~~
~
~
I~~
8701
thermal [3 + 21 cycloaddition of a substituted dialkoxy trimethylenemethane (TMM, 2) to an electron-deficient olefin proceeds endo-stereoselectively with retention of the olefin geometry, providing a single-step synthesis of substituted cyclopentanes (Scheme I). Some examples of successful regiocontrol in the cycloaddition to unsymmetrical olefins are also described. The present cycloaddition of a 4r-electron T M M to an olefin3 shares an important characteristic with the Diels-Alder reaction in that the reaction proceeds under predictable regio- and stereocontrol. We have previously shown4 that thermolysis of (E)ethylidenecyclopropane l a a t 60-100 OC reversibly and stereospecifically generates a dipolar, 4r-electron (E)-TMM 2a, which is stereochemically stable under the conditions of its [3 + 21 cycloaddition to olefins (vide infra).5 In order to investigate the stereochemical behavior of 2a in the cycloaddition, we examined its reaction with dimethyl maleate. When a 1 M CsD, solution of an equimolar mixture of l a and the maleate was heated a t 80 OC for 24 h under nitrogen, the ketene acetals (4a and 5a) were formed in 88% yield with a ratio of 955. By IH N M R analysis (3&H, NOE, and COSY) combined with chemical derivatization: the major isomer was assigned to be 4a. In no case did we note isomerization of either the starting olefin or the product under the reaction conditions. The stereochemsitry of the product in conjunction with the E geometry of 2a strongly suggested that the major cycloaddition pathway involves an endo transition state (3), wherein the acetal and the ester groups are located close to each other.' Various other observations (vide infra) are also consistent with the endo transition state. The stereoisomer 5a may be due to an alternative exo transition state. Several important observations were made. The endo:exo isomer ratio (4a:5a) exhibited notable dependence on the solvent polarity (Table I, entry l), decreasing dramatically from 97:3 to 73:278 as the polarity of the solvent was increased from octane (E = 1.9) to DMSO-ds (E = 46.6). The results suggest that polar interactions between the directing groups control the stereochemistry. This solvent dependency stands in contrast to the very small solvent effects in the Diels-Alder r e a ~ t i o n . Polar ~ solvent also accelerated the cycloaddition, which may be in part due to accelerated cycloaddition and in part due to accelerated TMM formation, which is about 100 times faster in DMSO than in an alkane ~ o l v e n t .The ~ product yield was little influenced by the solvent variation, however. The cycloadditions to methyl transcrotonate (entry 2) and methacrylate (entry 3) proceeded with virtually complete endo selectivity, but with poor regioselectivity. However, a high level of regiocontrol was achieved with the aid of substituent steric effects. Thus, the isopropyl TMM l b reacted with methyl trans-crotonate to give a single endo adduct, with other isomers accounting for only 4% of the cycloadducts (entry 4). On the other hand, a cis olefin reacts regio-randomly even with l b (entry S), and a bulky cis substituent on the olefin acceptor severely retards the cycloaddition (entry 7). These observations are also in agreement with the endo transition state 3. Alternabearing a bulky tively, methyl (E)-4,4-dimethyl-2-pentenoate, olefinic substituent, reacted with l a to give a single cycloadduct (>97% isomeric purity, entry 6). In general, an olefin substituent trans to the ester group appears to ensure high endo selectivity (3) Review: Nakamura, E. Organic Synthesis in Japan, Past, Present, and Future; Noyori, R., Ed.; Tokyo Kagaku Dozin: Tokyo, 1992; pp 273-282. (4) Nakamura, E.; Yamago, S.; Ejiri, S.; Dorigo, A. E.; Morokuma, K. J . Am. Chem. SOC.1991, 113, 3183. ( 5 ) Yamago, S.; Nakamura, E. J. Am. Chem. SOC.1989, 1 1 1 , 7285. Yamago, S.; Nakamura, E. J. Org. Chem. 1990, 55, 5553. (6) Stereochemistry in Table I was unequivocally established by NMR and/or chemical correlation, except in entries 3 and 5 (partially assigned and assigned by analogy, respectively). See the supplementary material for details. (7) Note that the structure of 3 is not meant to represent the exact geometry of the transition state, which may well be quite flexible. (8) Product ratios in Table I were determined by capillary GC and by ' H NMR. (9) Berson, J. A,; Hamlet, 2.; Mueller, W. A. J. Am. Chem. SOC.1962, 84, 297. Reichardt, C. Solvents and Solvent Effects in Organic Chemistry; VCH: Weinheim, Germany, 1988. Cf. Jung, M. E.; Gervay, J. J . Am. Chem. SOC.1989, I 1 I, 5469.
0002-7863/92/1514-8707$03.00/00 1992 American Chemical Society
J. Am. Chem. SOC.1992, 114, 8708-8710
8708
Table I. Regio- and Stereoselective 13 + 21 Cvcloaddition" ~~
entry 1
olefin E . COOMe, X
cycloadductsb
-
2 la
solvenf
C(OCH2CMe,CH,0)
1 la
+ f E ?Y
Ek
Octane (1.9) benzene (2:3) toluene (2.6) DME (7.2)
+&
&heme I
~~
%yield (product ratio) 77 (97:3)
ClCH C C l ( 1 0 4 DMF f 3 3 ) ' acetonitrile (37.5) 78 (80:20 DMSO-d6 (46.6) 73 (73:27{ toluene 81 (50:50)
3
a: R
Me, b: R
I
= i-Pr
-
4 (major)
5 (minor)
E COOMe
synthetic studies continue in these laboratories. Acknowledgment. We thank the Ministry of Education, Science, and Culture of Japan and the Yamada Science Foundation for financial support. Supplementary Material Available: Listings of experimental procedures, physical properties of the cycloadducts, and stereochemical assignments (17 pages). Ordering information is given on any current masthead page.
"The reactions were carried out at 100-120 O C for 55-75 h under nitrogen except in entries 1 and 2 (80 OC, 20-35 h). The yields are based on pure isolated products after hydrolysis of the ketene acetals except in entries 2, 5 , and 7, where they are based on N M R analysis. The product ratios were determined by capillary G C analysis on OV-1 or on OV-17. entry 5 , X = C(OCH2CH2CH,0). CThedielectric constants are for protio solvents: Gordon, A. J.; Ford, R. A. The Chemist's Companion; Wiley: New York, 1972.
even in a very polar solvent (cf. entries 4 and 6). Finally, we note that hydrolysis of the ketene acetal to the corresponding ester p r d s with high stereoselectivity (generally >90%). Thus, the cycloaddition and hydrolysis set four stereogenic centers with excellent stereocontrol.I0 In summary, we have found a general, stereospecific, regie and stereoselective thermal [ 3 23 cycloaddition reaction involving a 6r-electron transition state. The observed levels of selectivities may be better than those of its [4 21 counterpart, the uncatalyzed Diels-Alder reaction, and the reaction is unique among known all-carbon [3 21 cycloadditions.l3*J1 Mechanistic and
+
+
+
(10) Typical reaction procedure: Isopropylidenecyclopropane 1b and methyl crotonate (1.1 equiv) in CD,CN (0.5 mL/mmol of lb) were heated in a sealed tube at 100-120 OC for 50 h (>97% pure by capillary GC analysis). Careful NMR analyc8isindicated the regioisomeric ratio to be 96:4. Hydrolysis of the crude product (addition of 40 r L of 10% v/v aqueous AcOH) followed by purification on silica gel afforded a 95:3:2 isomeric mixture of cyclopentanecarboxylic acid ester i in 71% yield. This isomeric ratio indicates that the hydrolysis proceeded with >30: 1 selectivity. The cycloaddition reaction is remarkably insensitive to the reaction conditions, and the acetals derived from neopentyl glycol and 1.3-propanediol (Table I, entry 5 ) may be employed with equal success. O W O X O H
(1 I ) There is one previous report of endo-selective thermal [3 + 21 cycloaddition of TMM (with 3:l selectivity): Little, L. D.; Bukhari, A.; Venegas, M. G. Tetrahedron Letf. 1979, 305.
Photochemistry of a-Keto Phosphate Esters: Photorelease of a Caged cAMP Richard S. Givens,* Phillip S. Athey, L. William Kueper 111, Bogdan Matuszewski, and Jie-you Xue Department of Chemistry The University of Kansas Lawrence, Kansas 66045 Received June 29, 1992
We report our results on a phosphate photoprotecting (or cage) group that rapidly releases phosphate ( k , > lo8 s-I) in nearly quantitative yield by efficient photolysis of the caged phosphate. As a demonstration of this strategy, cAMP was generated with an efficiency of 34% and a first-order rate constant of 3 X lo8 s-I by irradiation of benzoin CAMP, a caged nucleotide. The recent interest in caged phosphates as precursors capable of rapid release of nucleotides and other biologically active phosphates to study the kinetics of muscle action by ATP,I calcium channel activation by GTP,* and visual excitation by the inositol phosphate cascade3 has drawn attention to the need for better photolabile group^.^ To date, the most commonly chosen cage (1) (a) Arner, A.; Goody, R. S.; Rapp, G.; Ruegg, J. C. J. Muscle Res. Cell Motil. 1987.8, 377-385. (b) Somlyo, A. V.; Goldman, Y. E.; Fujimori, T.; Bond, M.; Trentham, D. R.; Somlyo, A. P. J. Gen. Physiol. 1988, 91, 165-192. (c) McCray, J. A.; Trentham, D. R. Annu. Reo. Biophys. Biophys. Chem. 1989, 18, 239-270. (d) Kuhn, H.; Tewes, A.; Gagelmann, M.; Guth, K.; Arner, A.; Ruegg, J. C. Pfluegers Arch. 1990, 416, 512-518. (2) Dolphin, A. C.; Wootton, J. F.; Scott, R. H.; Trentham, D. R. Pfluegers Arch. 1988, 411, 628-636. (3) (a) Frank, T. M.; Fein, A. J. Gen. Physiol. 1991, 97, 697-723. (b) Walker, J. W.; Feeney, J.; Trentham, D. R. Biochemisfry 1989, 28, 3272-3280. (4) (a) Engels, J.; Schlaeger, E. J. Med. Chem. 1977, 20, 907; Experientia 1978, 34, 14-15. (b) Nerbonne, J. M.; Richard, S.; Nargeot, J.; Lester, H. A. Nature 1984,310, 74. (c) Nargeot, J.; Nerbonne, J. M.; Engels, J.; Lester, H. A. Proc. N a f l . Acad. Sci. U.S.A. 1983, 80, 2395. (d) Kaplan, J. H.; Forbush, B.; Hoffman, J. B. Biochemistry 1978, 17, 1929. (e) McCray, J. A.; Trentham, D. R.; Reid, G. P.; Walker, J. W. J. Am. Chem. SOC.1988, 110.7170. (0 McCray, J. A.;Trentham, D. R. Annu. Reo. Biophys. Chem. 1989, 18, 239.
0002-7863/92/1514-8708%03.00/00 1992 American Chemical Society
